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Inflammatory stimuli administered to humans and laboratory animals affect mesolimbic and nigrostriatal dopaminergic pathways in association with impaired motivation and motor activity. Alterations in dopaminergic corticostriatal reward and motor circuits have also been observed in depressed patients with increased peripheral inflammatory markers. The effects of peripheral inflammation on dopaminergic pathways and associated neurobiologic mechanisms and consequences have been difficult to measure in patients. Postmortem tissue (n = 11) from an established, translationally-relevant non-human primate model of cytokine-induced depressive behavior involving chronic interferon-alpha (IFN-a) administration was utilized herein to explore the molecular mechanisms of peripheral cytokine effects on striatal dopamine. Dopamine (but not serotonin or norepinephrine) was decreased in the nucleus accumbens (NAcc) and putamen of IFN-a-treated animals (p < 0.05). IFN-a had no effect on number of striatal neurons or dopamine terminal density, suggesting no overt neurodegenerative changes. RNA sequencing examined in the caudate, putamen, substantia nigra, and prefrontal cortical subregions revealed that while IFN-a nominally up-regulated limited numbers of genes enriching inflammatory signaling pathways in all regions, robust, whole genome-significant effects of IFN-a were observed specifically in putamen. Genes upregulated in the putamen primarily enriched synaptic signaling, glutamate receptor signaling, and inflammatory/metabolic pathways downstream of IFN-a, including MAPK and PI3K/AKT cascades. Conversely, gene transcripts reduced by IFN-a enriched oxidative phosphorylation (OXPHOS), protein translation, and pathways regulated by dopamine receptors. Unsupervised clustering identified a gene co-expression module in the putamen that was associated with both IFN-a treatment and low dopamine levels, which enriched similar inflammatory, metabolic, and synaptic signaling pathways. IFN-a-induced reductions in dopamine further correlated with genes related to excitotoxic glutamate, kynurenine, and altered dopamine receptor signaling (r = 0.78-97, p < 0.05). These findings provide insight into the immunologic mechanisms and neurobiological consequences of peripheral inflammation effects on dopamine, which may inform novel treatment strategies targeting inflammatory, metabolic or neurotransmitter systems in depressed patients with high inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Inflammatory biomarkers like C-reactive protein (CRP) are elevated in a subset of patients with depression and have been associated with lower functional connectivity (FC) in a ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuit and symptoms of anhedonia. Evidence linking these relationships to the effects of inflammation on dopamine is consistent with our recent findings that acute levodopa (L-DOPA) increased VS-vmPFC FC in association with deceased anhedonia in depressed patients with higher but not lower CRP (>2 versus ≤ 2 mg/L). To determine whether repeated L-DOPA administration caused sustained effects on FC and behavior in these patients, medically stable depressed outpatients with CRP > 2 mg/L and anhedonia (n = 18) received one week of three doses of L-DOPA (150-450 mg/day/week with carbidopa) or placebo in a randomized order. Resting-state (rs) and task-based (tb; monetary incentive delay) fMRI, effort-based motivation, and exploratory measures of anhedonia and depression severity were assessed at baseline and after one week of placebo and each dose of L-DOPA. Responses to individual doses of L-DOPA varied across outcomes. For example, VS-vmPFC rs-FC was significantly increased by L-DOPA at 150 and 450 mg/day/week (p < 0.01), whereby approximately half of patients responded optimally to 150 mg/day L-DOPA and approximately half required higher doses for maximum effect. While effort-based motivation was only significantly increased by L-DOPA at 150 mg/day (p < 0.05), it correlated with VS-vmPFC rs-FC at this dose (r = 0.64, p = 0.024), and all L-DOPA doses met a clinically significant threshold of ≥ 10 % increase versus placebo. When comparing the maximum response at any L-DOPA dose to placebo, high effect sizes were observed for these primary outcomes and tb-FC during reward anticipation (d z  = 0.82-0.98, p < 0.01), as well as secondary and exploratory measures of anhedonia and depression severity (d z  = 0.48-0.97, p < 0.05). Sustained effects on reward circuitry, effort-based motivation, and anhedonia by repeated L-DOPA administration support the therapeutic potential of agents that increase dopamine in depressed patients with higher inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein >3 mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5 mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dorsomedial prefrontal cortex (dmPFC), ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Inflammation is one biological pathway thought to impact the brain to contribute to major depressive disorder (MDD) and is reliably associated with resistance to standard antidepressant treatments. While peripheral immune cells, particularly monocytes, have been associated with aspects of increased inflammation in MDD and symptom severity, significant gaps in knowledge exist regarding the mechanisms by which these cells are activated to contribute to behavioral symptoms in MDD. One concept that has gained recent appreciation is that metabolic rewiring to glycolysis in activated myeloid cells plays a crucial role in facilitating these cells' pro-inflammatory functions, which may underlie myeloid contribution to systemic inflammation and its effects on the brain. Given emerging evidence from translational studies of depression that peripheral monocytes exhibit signs of glycolytic activation, better understanding the immunometabolic phenotypes of monocytes which are known to be elevated in MDD with high inflammation is a critical step toward comprehending and treating the impact of inflammation on the brain. This narrative review examines the extant literature on glycolytic metabolism of circulating monocytes in depression and discusses the functional implications of immunometabolic shifts at both cellular and systemic levels. Additionally, it proposes potential therapeutic applications of existing immunomodulators that target glycolysis and related metabolic pathways in order to reverse the impact of elevated inflammation on the brain and depressive symptoms., Competing Interests: None., (© 2024 The Author.)

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein > 3mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dmPFC, ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.

Psychosocial stress has been shown to prime peripheral innate immune cells, which take on hyper-inflammatory phenotypes and are implicated in depressive-like behavior in mouse models. However, the impact of stress on cellular metabolic states that are thought to fuel inflammatory phenotypes in immune cells are unknown. Using single cell RNA-sequencing, we investigated mRNA enrichment of immunometabolic pathways in innate immune cells of the spleen in mice subjected to repeated social defeat stress (RSDS) or no stress (NS). RSDS mice displayed a significant increase in the number of splenic macrophages and granulocytes (p < 0.05) compared to NS littermates. RSDS-upregulated genes in macrophages, monocytes, and granulocytes significantly enriched immunometabolic pathways thought to play a role in myeloid-driven inflammation (glycolysis, HIF-1 signaling, MTORC1 signaling) as well as pathways related to oxidative phosphorylation (OXPHOS) and oxidative stress (p < 0.05 and FDR<0.1). These results suggest that the metabolic enhancement reflected by upregulation of glycolytic and OXPHOS pathways may be important for cellular proliferation of splenic macrophages and granulocytes following repeated stress exposure. A better understanding of these intracellular metabolic mechanisms may ultimately help develop novel strategies to reverse the impact of stress and associated peripheral immune changes on the brain and behavior., Competing Interests: None, (© 2023 Published by Elsevier Inc.)

Microphysiological system or organ-on-a-chip technologies can replicate the key structure and function of 3D human tissues with higher reproducibility than less controllable 3D cell aggregate models, providing great potential to become advanced drug toxicity and efficacy test platforms alternative to animal models. However, these organ chip models remain to be manufactured and standardized in a highly reproducible manner for reliable drug screening and mechanism of action research. Herein, we present a manufactured form of 'micro-engineered physiological system-tissue barrier chip' called MEPS-TBC for the highly replicable modeling of the human blood-brain barrier (BBB) with a 3D perivascular space. The perivascular region was controlled by tunable aspiration, where human astrocytes reside in 3D, create a network, and communicate with human pericytes facing human vascular endothelial cells, thereby replicating the 3D BBB. The lower channel structure of MEPS-TBC was designed and optimized using a computational simulation to facilitate aspiration while maintaining multicellular construction. Our human BBB model of the 3D perivascular unit and the endothelium perfused by physiological shear stress secured significantly enhanced barrier function exhibiting greater TEER and lower permeability, compared to the only endothelial model, indicating that the cellular interactions between BBB cells significantly contribute to the BBB formation. Importantly, our BBB model showed the cellular barrier function for homeostatic trafficking regulation against inflammatory peripheral immune cells, as well as for molecular transport control across the BBB. We believe our manufactured chip technology will construct reliable and standardized organ-chip models for disease mechanism research and predictive drug screening.

Findings from numerous laboratories and across neuroimaging modalities have consistently shown that exogenous administration of cytokines or inflammatory stimuli that induce cytokines disrupts circuits and networks involved in motivation and motor activity, threat detection, anxiety, and interoceptive and emotional processing. While inflammatory effects on neural circuits and relevant behaviors may represent adaptive responses promoting conservation of energy and heightened vigilance during immune activation, chronically elevated inflammation may contribute to symptoms of psychiatric illnesses. Indeed, biomarkers of inflammation such as cytokines and acute phase reactants are reliably elevated in a subset of patients with unipolar or bipolar depression, anxiety-related disorders, and schizophrenia and have been associated with differential treatment responses and poor clinical outcomes. A growing body of literature also describes higher levels of endogenous inflammatory markers and altered, typically lower functional or structural connectivity within these circuits in association with transdiagnostic symptoms such as anhedonia and anxiety in psychiatric and at-risk populations. This review presents recent evidence that inflammation and its effects on the brain may serve as one molecular and cellular mechanism of dysconnectivity within anatomically and/or functionally connected cortical and subcortical regions in association with transdiagnostic symptoms. We also discuss the need to establish reproducible methods to assess inflammation-associated dysconnectivity in relation to behavior for use in translational studies or biomarker-driven clinical trials for novel pharmacological or behavioral interventions targeting inflammation or its effects on the brain., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine. To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart). The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach. Data available both pre- and post-challenge (n = 31/40) established stability of rsFC across visits and determined CRP > 2 mg/L as a cut-point for patients exhibiting positive FC responses (post minus pre) to L-DOPA versus placebo (p < 0.01). Higher post-L-DOPA FC in patients with CRP > 2 mg/L was confirmed in all patients (n = 40) where rsFC data were available post-challenge (B = 0.15, p = 0.006), and in those with task-based (tb)FC during reward anticipation (B = 0.15, p = 0.013). While effort-based motivation outside the scanner positively correlated with rsFC independent of treatment or CRP, change in anhedonia scores negatively correlated with rsFC after L-DOPA only in patients with CRP > 2 mg/L (r = -0.56, p = 0.012). FC in reward circuitry should be further validated in larger samples as a biomarker of target engagement for potential treatments including dopaminergic agents in MDD patients with increased inflammation., (© 2022. The Authors.)

Objective: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women., Methods: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates., Results: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation., Conclusions: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

Inflammation is associated with symptoms of anhedonia, a core feature of major depression (MD). We have shown that MD patients with high inflammation as measured by plasma C-reactive protein (CRP) and anhedonia display gene signatures of metabolic reprograming (e.g., shift to glycolysis) necessary to sustain cellular immune activation. To gain preliminary insight into the immune cell subsets and transcriptomic signatures that underlie increased inflammation and its relationship with behavior in MD at the single-cell (sc) level, herein we conducted scRNA-Seq on peripheral blood mononuclear cells from a subset of medically-stable, unmedicated MD outpatients. Three MD patients with high CRP (>3 mg/L) before and two weeks after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab and three patients with low CRP (≤3 mg/L) were studied. Cell clusters were identified using a Single Cell Wizard pipeline, followed by pathway analysis. CD14 + and CD16 + monocytes were more abundant in MD patients with high CRP and were reduced by 29% and 55% respectively after infliximab treatment. Within CD14 + and CD16 + monocytes, genes upregulated in high CRP patients were enriched for inflammatory (phagocytosis, complement, leukocyte migration) and immunometabolic (hypoxia-inducible factor [HIF]-1, aerobic glycolysis) pathways. Shifts in CD4 + T cell subsets included ∼30% and ∼10% lower abundance of CD4 + central memory (T CM ) and naïve cells and ∼50% increase in effector memory-like (T EM-like ) cells in high versus low CRP patients. T CM cells of high CRP patients displayed downregulation of the oxidative phosphorylation (OXPHOS) pathway, a main energy source in this cell type. Following infliximab, changes in the number of CD14 + monocytes and CD4 + T EM-like cells predicted improvements in anhedonia scores (r = 1.0, p < 0.001). In sum, monocytes and CD4 + T cells from MD patients with increased inflammation exhibited immunometabolic reprograming in association with symptoms of anhedonia. These findings are the first step toward determining the cellular and molecular immune pathways associated with inflammatory phenotypes in MD, which may lead to novel immunomodulatory treatments of psychiatric illnesses with increased inflammation., (© 2022 The Authors.)

Background: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions., Methods: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism., Results: The IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids., Conclusion: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Anhedonia, characterized by a lack of motivation, interest, or ability to experience pleasure, is a prominent symptom of depression and other psychiatric disorders and has been associated with poor response to standard therapies. One pathophysiologic pathway receiving increased attention for its potential role in anhedonia is inflammation and its effects on the brain. Exogenous administration of inflammatory stimuli to humans and laboratory animals has reliably been found to affect neurotransmitters and neurocircuits involved in reward processing, including the ventral striatum and ventromedial prefrontal cortex, in association with reduced motivation. Moreover, a rich literature including meta-analyses describes increased inflammation in a significant proportion of patients with depression and other psychiatric illnesses involving anhedonia, as evident by elevated inflammatory cytokines, acute phase proteins, chemokines, and adhesion molecules in both the periphery and central nervous system. This endogenous inflammation may arise from numerous sources including stress, obesity or metabolic dysfunction, genetics, and lifestyle factors, many of which are also risk factors for psychiatric illness. Consistent with laboratory studies involving exogenous administration of peripheral inflammatory stimuli, neuroimaging studies have further confirmed that increased endogenous inflammation in depression is associated with decreased activation of and reduced functional connectivity within reward circuits involving ventral striatum and ventromedial prefrontal cortex in association with anhedonia. Here, we review recent evidence of relationships between inflammation and anhedonia, while highlighting translational and mechanistic work describing the impact of inflammation on synthesis, release, and reuptake of neurotransmitters like dopamine and glutamate that affects circuits to drive motivational deficits. We will then present insight into novel pharmacological strategies that target either inflammation or its downstream effects on the brain and behavior. The meaningful translation of these concepts through appropriately designed trials targeting therapies for psychiatric patients with high inflammation and transdiagnostic symptoms of anhedonia is also discussed., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Inflammation impacts basal ganglia motor circuitry in association with psychomotor retardation, a key symptom of major depression (MD). We previously reported associations between circulating protein inflammatory biomarkers and psychomotor slowing as measured by neuropsychological tests probing psychomotor speed in patients with MD. To discover novel transcriptional signatures in peripheral blood immune cells related to psychomotor slowing, microarray data were analyzed in a primary cohort of 88 medically-stable, unmedicated, ambulatory MD patients. Results were confirmed and extended in a second cohort of 57 patients with treatment resistant depression (TRD) before and after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab versus placebo. Composite scores reflecting pure motor and cognitive-motor processing speed were linearly associated with 403 and 266 gene transcripts in each cohort, respectively (|R| > 0.30, p < 0.01), that were enriched for cytokine signaling and glycolysis-related pathways (p < 0.05). Unsupervised clustering in the primary cohort revealed two psychomotor slowing-associated gene co-expression modules that were enriched for interferon, interleukin-6, aerobic glycolysis, and oxidative phosphorylation pathways (p < 0.05, q < 0.1). Transcripts were predominantly derived from monocytes, plasmacytoid dendritic cells, and natural killer cells (p's < 0.05). In infliximab-treated TRD patients with high plasma C-reactive protein concentrations (>5 mg/L), two differential co-expression modules enriched for oxidative stress and mitochondrial degradation were associated with improvements in psychomotor reaction time (p < 0.05). These results indicate that inflammatory signaling and associated metabolic reprogramming in peripheral blood immune cells are associated with systemic inflammation in depression and may affect relevant brain circuits to promote psychomotor slowing., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid. Neuroimaging data indicate that these inflammation-induced neurotransmitter effects manifest as decreased activation of ventral striatum and decreased functional connectivity in reward circuitry involving ventral striatum and ventromedial prefrontal cortex. Neurocircuitry changes in turn mediate nuanced effects on motivation that include decreased willingness to expend effort for reward while maintaining the ability to experience reward. Taken together, the data reveal an inflammation-induced pathophysiologic phenotype that is agnostic to diagnosis. Given the many mechanisms involved, this phenotype represents an opportunity for development of novel and/or repurposed pharmacological strategies that target inflammation and associated cellular and systemic immunometabolic changes and their downstream effects on the brain. To date, clinical trials have failed to capitalize on the unique nature of this transdiagnostic phenotype, leaving the field bereft of interpretable data for meaningful clinical application. However, novel trial designs incorporating established targets in the brain and/or periphery using relevant outcome variables (e.g., anhedonia) are the future of targeted therapy in psychiatry. SIGNIFICANCE STATEMENT: Emerging understanding of mechanisms by which peripheral inflammation can affect the brain and behavior has created unprecedented opportunities for development of pharmacological strategies to treat deficits in motivation including anhedonia, a core and disabling symptom of depression well represented in multiple psychiatric disorders. Mechanisms include inflammation and cellular and systemic immunometabolism and alterations in dopamine, glutamate, and kynurenine metabolites, revealing a target-rich environment that nevertheless has yet to be fully exploited by current clinical trial designs and drugs employed., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Adolescent exposure to chronic stress, a risk factor for mood disorders in adulthood, sensitizes the neuroinflammatory response to a subsequent immune challenge. We previously showed that chronic adolescent stress (CAS) in rats led to distinct patterns of neuroimmune priming in adult male and female rats. However, sex differences in the neuroimmune consequences of CAS and their underlying mechanisms are not fully understood. Here we hypothesized that biological sex would dictate differential induction of inflammation-related transcriptomic pathways and immune cell involvement (microglia activation and leukocyte presence) in the hippocampus of male and female rats with a history of CAS. Adolescent rats underwent CAS (six restraint and six social defeat episodes during postnatal days 38-49), and behavioral assessments were conducted in adolescence and adulthood. Neuroimmune measures were obtained following vehicle or a systemic lipopolysaccharide (LPS) challenge in adulthood. CAS led to increased time in the corners of the open field in adolescence. In males, CAS also increased social avoidance. As adults, CAS rats displayed an exaggerated enrichment of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway and chemokine induction following LPS challenge, and increased number of perivascular CD45 + cells in the hippocampus. However, CAS females, but not males, showed exaggerated glucocorticoid receptor (GR) pathway enrichment and increased microglial complexity. These results provide further insight to the mechanisms by which peripheral immune events may influence neuroimmune responses differentially among males and females and further demonstrate the importance of adolescent stress in shaping adult responses.

Bidirectional relationships between inflammation and metabolic dysfunction may contribute to the pathophysiology of psychiatric illnesses like depression. Metabolic disturbances drive inflammation, which in turn exacerbate metabolic outcomes including insulin resistance. Both inflammatory (e.g. endotoxin, vaccination) and metabolic challenges (e.g. glucose ingestion) have been shown to affect activity and functional connectivity (FC) in brain regions that subserve reward and motor processing. We previously reported relationships between elevated concentrations of endogenous inflammatory markers including C-reactive protein (CRP) and low corticostriatal FC, which correlated with symptoms of anhedonia and motor slowing in major depression (MD). Herein, we examined whether similar relationships were observed between plasma markers related to glucose metabolism (non-fasting concentrations of glucose, insulin, leptin, adiponectin and resistin) in 42 medically-stable, unmedicated MD outpatients who underwent fMRI. A targeted, hypothesis-driven approach was used to assess FC between seeds in subdivisions of the ventral and dorsal striatum and a region in ventromedial prefrontal cortex (VS-vmPFC), which was previously found to correlate with both inflammation and symptoms of anhedonia and motor slowing. Associations between FC and gene expression signatures were also explored. A composite score of all 5 glucose-related markers (with increasing values reflecting higher concentrations) was negatively correlated with both ventral striatum (VS)-vmPFC (r = -0.33, p < 0.05) and dorsal caudal putamen (dcP)-vmPFC (r = -0.51, p < 0.01) FC, and remained significant after adjusting for covariates including body mass index (p < 0.05). Moreover, an interaction between the glucose-related composite score and CRP was observed for these relationships (F[2,33] = 4.3, p < 0.05) whereby significant correlations between the glucose-related metabolic markers and FC was found only in patients with high plasma CRP (>3 mg/L; r = -0.61 to -0.81, p < 0.05). Insulin and resistin were the individual markers most predictive of VS-vmPFC and dcP-mPFC FC, respectively, and insulin, resistin and CRP clustered together and in association with both LV-vmPFC and dcP-vmPFC in principal component analyses. Exploratory whole blood gene expression analyses also confirmed that gene probes negatively associated with FC were enriched for both inflammatory and metabolic pathways (FDR p < 0.05). These results provide preliminary evidence that inflammation and metabolic dysfunction contribute jointly to deficits in reward and motor circuits in MD. Future studies using fasting samples and longitudinal and interventional approaches are required to further elucidate the respective contributions of inflammation and metabolic dysfunction to circuits and symptoms relevant to motivation and motor activity, which may have treatment implications for patients with psychiatric illnesses like depression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n = 93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n = 30, 33rd percentile) versus Low (n = 32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q < 0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n = 10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z = 2.95, p < 0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n = 20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n = 93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronic adolescent stress alters behavior in a sex-specific manner at the end of adolescence and in adulthood. Although prolonged behavioral repercussions of chronic adolescent stress have been documented, the potential underlying mechanisms are incompletely understood. In this study we demonstrate that a history of chronic adolescent stress modified the adult stress response, as measured by corticosterone concentration, such that a history of chronic adolescent stress resulted in a blunted response to a novel acute stressor. In order to begin to address potential mechanistic underpinnings, we assessed the extent to which chronic adolescent stress impacted global DNA methylation. Reduced global hippocampal methylation was evident in females with a history of chronic adolescent stress; thus, it was possible that chronic adolescent stress altered global transcription in the whole hippocampi of adult male and female rats. In addition, because acute stress can stimulate a genomic response, we assessed the transcriptome following exposure to an acute novel stressor to determine the extent to which a history of chronic adolescent stress modifies the adult transcriptional response to an acute stressor in males and females. In addition to the reduction in global methylation, chronic adolescent stress resulted in distinct patterns of gene expression in the adult hippocampus that differentiated by sex. Furthermore, both sex and a history of chronic adolescent stress influenced the transcriptional response to an acute novel stressor in adulthood, suggesting both latent and functional effects of chronic adolescent stress at the level of gene transcription. Pathway analysis indicated that ESR1 and IFN-α may be particularly influential transcription factors mediating these transcriptional differences and suggest candidate mechanisms for future studies. Collectively, these studies demonstrate sex-specific and enduring effects of adolescent stress exposure that are more pronounced in females than in males.

Adversity during development is a reliable predictor of psychiatric disorders such as depression and anxiety which are increasingly recognized to have an immune component. We have previously demonstrated that chronic adolescent stress (CAS) in rats leads to depressive-like behavior in adulthood along with long-lasting changes to the hypothalamic-pituitary-adrenal axis and pro-inflammatory cytokine induction in the hippocampus. However, the mechanisms by which CAS promotes hippocampal inflammation are not yet defined. Here we tested the hypothesis that a history of CAS exaggerates induction of the pro-inflammatory NFκB pathway in the adult rat hippocampus without compromising the peripheral immune response. We also assessed potential sex differences because it is unclear whether females, who are twice as likely to suffer from mood disorders as males, are disproportionally affected by stress-primed inflammation. Male and female adolescent rats underwent a CAS paradigm or received no stress. Six weeks following the last stressor, all rats received a single systemic injection of either lipopolysaccharide or vehicle to unmask possible immune-priming effects of CAS. An NFκB signaling PCR array demonstrated that CAS exaggerated the expression of NFκB-related genes in the hippocampus of both males and females. Interestingly, targeted qPCR demonstrated that CAS potentiated the induction of hippocampal IL1B and REL mRNA in female rats only, suggesting that some immune effects of CAS are indeed sex-specific. In contrast to the hippocampal findings, indices of peripheral inflammation such as NFκB activity in the spleen, plasma IL-1β, IL-6, TNF-α, and corticosterone were not impacted by CAS in female rats. Despite showing no pro-inflammatory changes to hippocampal mRNA, male CAS rats displayed lower plasma corticosterone response to LPS at 2 h after injection followed by an exaggerated plasma IL-1β response at 4 h. This potentially blunted corticosterone response coupled with excessive innate immune signaling in the periphery is consistent with possible glucocorticoid resistance in males. In contrast, the effects of CAS manifested as excessive hippocampal immune reactivity in females. We conclude that while a history of exposure to chronic adolescent stress enhances adult immune reactivity in both males and females, the mechanism and manifestation of such alterations are sex-specific., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The tumor necrosis factor (TNF) antagonist infliximab was previously found to reduce depressive symptoms in patients with treatment-resistant major depression (TRD) who exhibited high baseline inflammation, as reflected by plasma C-reactive protein (CRP) >5 mg/L. Further predictors of antidepressant response to infliximab included differential expression of peripheral blood gene transcripts that were related not only to inflammation but also to glucose and lipid metabolism. To determine whether plasma biomarkers of glucose and lipid metabolism were similarly associated with antidepressant response to infliximab and with relevant gene transcripts, we measured concentrations of glucose, insulin, and protein hormones that regulate glucose homeostasis and metabolism (leptin, resistin, and adiponectin), as well as cholesterols, triglycerides, and non-esterified fatty acids (NEFA), in medically-stable TRD outpatients at baseline and 2 weeks after the first infusion of infliximab (n = 26) or placebo (n = 26). Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. We found that baseline cholesterol (total, low-density lipoprotein [LDL], and non-high-density lipoprotein [non-HDL]), triglycerides and NEFA were elevated in patients who exhibited an antidepressant response to infliximab (all p < 0.05) but not placebo (all p > 0.299). HDL and non-HDL cholesterol concentrations also correlated with two lipid-related gene transcripts that were predictive of antidepressant response (r = 0.33 to 0.39, p < 0.05). Although not associated with response to infliximab, resistin correlated with numerous glucose-related transcripts (r = -0.32 to 0.37, p < 0.05) and was higher at 2 weeks post-infusion in patients treated with infliximab compared to placebo (p = 0.028). Concentrations of cholesterol (total, LDL, HDL, non-HDL) were also lower at 2 weeks in patients treated with infliximab compared to placebo, but only in those patients with CRP >5 mg/L at baseline (all p < 0.05). These results are consistent with previous work showing that high inflammation in patients with depression is associated with metabolic alterations, which together predict response to both traditional and experimental antidepressant therapies. Additionally, our findings suggest a causal relationship between increased inflammation and high cholesterol in depression, as a single infusion of infliximab reduced cholesterol in TRD patients with high CRP compared to placebo., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Chronic inflammation caused by HIV infection may lead to deficient glucocorticoid (GC) signaling predisposing people living with HIV to depression and other psychiatric disorders linked to GC resistance. We hypothesized that comorbid HIV and depressive symptoms in women would synergistically associate with deficits in GC signaling. This cross-sectional study used samples obtained from the Women's Interagency HIV Study (WIHS). The Centers for Epidemiological Studies (CES-D) was used to define depression in four groups of women from the Women's Interagency HIV Study (WIHS): 1) HIV-negative, non-depressed (n = 37); 2) HIV-negative, depressed (n = 34); 3) HIV-positive, non-depressed (n = 38); and 4) HIV-positive, depressed (n = 38). To assess changes in GC signaling from peripheral blood mononuclear cells (PBMCs), we examined baseline and dexamethasone (Dex)-stimulated changes in the expression of the GC receptor (GR, gene: Nr3c1) and its negative regulator Fkbp5 via quantitative RT-PCR. GR sensitivity was evaluated in vitro by assessing the Dex inhibition of lipopolysaccharide (LPS)-stimulated IL-6 and TNF-α levels. Depressive symptoms and HIV serostatus were independently associated with elevated baseline expression of Fkbp5 and Nr3c1. Depressive symptoms, but not HIV status, was independently associated with reduced LPS-induced release of IL-6. Counter to predictions, there was no interactive association of depressive symptoms and HIV on any outcome. Comorbid depressive symptoms with HIV infection were associated with a gene expression and cytokine profile similar to that of healthy control women, a finding that may indicate further disruptions in disease adaptation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Accurate assessment of plasma corticosterone, the primary stress hormone in rodents, is an essential part of characterizing the stress response in experimental animals. To this end, both enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) remain widely used. However, considerable assay-specific variability exists among commercially available corticosterone assays due to differing assay principles, detection methods, range, and sensitivity. While technical comparisons of commercially available corticosterone assays have previously been conducted, the ability to detect acute stress-induced endocrine changes has not been compared among these methods to date. Using the forced swim test, a commonly utilized behavioral paradigm in rodents as a physiologically-relevant acute stress challenge, we compared four commercial corticosterone assays - three ELISA kits and one RIA kit - in their ability to detect corticosterone across a dynamic range of both baseline and acute swim stress-driven concentrations. While all methods yielded results that were consistent at measuring relative differences between samples, only two of the four assays evaluated detected a statistically significant increase in corticosterone in rats exposed to acute swim stress compared to rats at baseline. The ELISA kit from Enzo Life Sciences demonstrated the greatest percent increase in plasma corticosterone from baseline to acute stress conditions. The RIA kit from MP Biomedicals also detected a significant corticosterone increase and yielded higher concentrations of corticosterone both at baseline and in the acute stress condition relative to the other three assays. We conclude that choice of assay can impact interpretation of data due to differences in efficacy across a dynamic range of physiological concentrations of corticosterone., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Women appear to be more vulnerable to the depressogenic effects of inflammation than men. Chronic stress, one of the most pertinent risk factors of depression and anxiety, is known to induce behavioral and affective-like deficits via neuroimmune alterations including activation of the brain's immune cells, pro-inflammatory cytokine expression, and subsequent changes in neurotransmission and synaptic plasticity within stress-related neural circuitry. Despite well-established sexual dimorphisms in the stress response, immunity, and prevalence of stress-linked psychiatric illnesses, much of current research investigating the neuroimmune impact of stress remains exclusively focused on male subjects. We summarize and evaluate here the available data regarding sex differences in the neuro-immune consequences of stress, and some of the physiological factors contributing to these differences. Furthermore, we discuss the extent to which sex differences in stress-related neuroinflammation can account for the overall female bias in stress-linked psychiatric disorders including major depressive disorder and anxiety disorders. The currently available evidence from rodent studies does not unequivocally support the peripheral inflammatory changes seen in women following stress. Replication of many recent findings in stress-related neuroinflammation in female subjects is necessary in order to build a framework in which we can assess the extent to which sex differences in stress-related inflammation contribute to the overall female bias in stress-related affective disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mutual regulation and balance between the endocrine and immune systems facilitate an organism's stress response and are impaired following chronic stress or prolonged immune activation. Concurrent alterations in stress physiology and immunity are increasingly recognized as contributing factors to several stress-linked neuropsychiatric disorders including depression, anxiety, and post-traumatic stress disorder. Accumulating evidence suggests that impaired balance and crosstalk between the glucocorticoid receptor (GR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) - effectors of the stress and immune axes, respectively - may play a key role in mediating the harmful effects of chronic stress on mood and behavior. Here, we first review the molecular mechanisms of GR and NFκB interactions in health, then describe potential shifts in the GR-NFκB dynamics in chronic stress conditions within the context of brain circuitry relevant to neuropsychiatric diseases. Furthermore, we discuss developmental influences and sex differences in the regulation of these two transcription factors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57Bl/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Highly active antiretroviral therapy (HAART) has improved prognosis for people living with HIV (PLWH) and dramatically reduced the incidence of AIDS. However, even when viral load is controlled, PLWH develop psychiatric and neurological disorders more frequently than those living without HIV. Adolescents with HIV are particularly susceptible to the development of psychiatric illnesses and neurocognitive impairments. While both psychiatric and neurocognitive disorders have been found to be exacerbated by stress, the extent to which chronic stress and HIV-1 viral proteins interact to impact behavior and relevant neuroinflammatory processes is unknown. Determination of the individual contributions of stress and HIV to neuropsychiatric disorders is heavily confounded in humans. In order to isolate the influence of HIV-1 proteins and chronic stress on behavior and neuroinflammation, we employed the HIV-1 transgenic (Tg) rat model, which expresses HIV-1 proteins with a gag and pol deletion, allowing for viral protein expression without viral replication. This Tg line has been characterized as a model of HAART-controlled HIV-1 infection due to the lack of viral replication but continued presence of HIV-1 proteins. We exposed male and female adolescent HIV-1 Tg rats to a mixed-modality chronic stress paradigm consisting of isolation, social defeat and restraint, and assessed behavior, cerebral vascularization, and neuroinflammatory endpoints. Stress, sex, and presence of the HIV-1 transgene impacted weight gain in adolescent rats. Female HIV-1 Tg rats showed decreases in central tendency during the light cycle in the open field regardless of stress exposure. Both male and female HIV-1 Tg rats exhibited decreased investigative behavior in the novel object recognition task, but no memory impairments. Adolescent stress had no effect on the tested behaviors. Microglia in female HIV-1 Tg rats exhibited a hyper-ramified structure, and gene expression of complement factor B was increased in the hippocampus. In addition, adolescent stress exposure increased microglial branching and junctions in female wild-type rats without causing any additional increase in HIV-1 rats. These data suggest that the presence of HIV-1 proteins during development leads to alterations in behavioral and neuroinflammatory endpoints that are not further impacted by concurrent chronic adolescent stress.

Euthanasia by anesthetic agents is commonly performed prior to tissue collection in order to minimize pain and distress to the animal. However, depending on their mechanism of action as well as administration regimen, different methods of anesthesia may trigger an acute stress response through engaging the hypothalamic-pituitary-adrenal (HPA) axis, which can impact numerous other physiological processes that the researcher may wish to examine as endpoints. We investigated the effects of the commonly used anesthetic agent isoflurane on two different endpoints related to the stress response: plasma corticosterone levels and gene expression of the glucocorticoid receptor (GR) as well as several of its regulators including FK506-binding protein 51 (Fkbp5) in the hippocampus of male and female rats. Our results indicate that brief exposure to anesthesia by isoflurane prior to decapitation can alter plasma corticosterone levels differentially in male and female rats within minutes without impacting gene expression in the hippocampus. We conclude that collection methods can influence stress-related physiological endpoints in female rats and the potential influence of even brief anesthesia as well as sex differences in response to anesthesia should be evaluated during the experimental design process and data interpretation. This finding is particularly important in light of new NIH standards regarding sex and reproducibility, and care should be taken to be certain that sex differences in endpoints of interest are not an artifact of sex differences in response to collection paradigms., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The incidence of depression and anxiety disorders is twice as high in women than men; however, females exhibit less neuronal damage following an equivalent ischemic event. Microembolic stroke increases anxiety- and depressive-like behaviors in male rats but the behavioral repercussions in females are unknown., Findings: Given the relative neuronal protection from stroke in ovary-intact females, female rats exposed to microembolic stroke may be behaviorally protected as compared to males. The data presented demonstrate that anxiety-like behavior is increased in males despite a comparable increase in microglial activation following microembolic stroke in both males and females., Conclusions: These data suggest that males may be more behaviorally susceptible to the effects of microembolic stroke and further illustrate a dissociation between neuroinflammation and behavior in females.